Iodine organic compounds for use as X-ray contrast compositions



.acid have an insuflicient Patented July 1, 1941 UNITED STATES PATENT oriucia'.v

IODiNE ORGANIC COMPOUNDS FOR USE AS X-RAY CONTRAST COMPOSITIONS llndr Gaston Jules Guerbet, Paris, France No Application January 21, 1938, Se-

rial No. 186,114. In France January 29, 19:3!

(Cl. 16'l95) After-cooling, the mixture thus obtained is poured into cold water. If necessary, a suflicient dose, and of local irritating action; furthermore,

they should exhibit selective elimination by the reins (in. the ease of intravenous urography). The compounds of this class,.which have been -hitherto proposed, contain two atoms of iodine per molecule, at the maximum. Applicant has discovered that certain compounds containing four atoms of iodine per 'moleculeand consisting of salts of the tet'raiodometaand tetraiodoparaphthalic acids possess valuable properties oi. X-ray contrast agents and meet the aforesaid requirements.

While the salts of the tetraiodo-orthophthalic solubility and are toxic, the salts of thetetraio'dometaand tetralodo-. paraphthalic acids are very soluble, and deprived 0! any toxic character.

The present invention comprises, as new chemical compounds, the tetraiodometa and tetraiodoparaphthalic acids Cali (COaH): and their. derivatives, as well as. the X-ray contrast compositions containing said acids or their' derivatives. The tetraiodometaphthalic acid, whose .develped iormula is-as i'ollows 'I-c sci-I I) 1- t to 160 -C., this temperature being maintained for about 8-hours.

The following reaction takes place: ctnncolm =+4so3+41= 1 v CBI4(CO2H) 2+2SO4Ha+2SO2 (2) The disengagement of sulphur dioxide resultin: Irom this reaction produces an abundant .ioam.

amount of sulphur dioxide is added to remove the excess of tree iodine. The insoluble compound which precipitates consists of-crude tetraiodo metaphthalic acid, This latter contains,

.as impurities, .hexa-iodo benzene and phthalic acids which are less iodized.

'The crude product is treated with a dilute solution of soda lye, in which the hexa iodo benzene remains insoluble. The alkaline solution, treated with an excess of sulphuric acid, yields a precipitate containing the desired acid, and less iodized acids.

Inforder to remove the less io'dizedacids", advantage is taken of the property which they possess, on the contrary to the tetraiodized acid,

of producing esters when boiled for several hours with methyl alcohol containing- 3% of hydrochloric acid.

The esters thus iormed are separated by heating the product in the dry state. The tetraiodometaphthalie acid remains as a residue. It is purified by crystallization irom dilute acetic acid. With regard to the tetraiodoparaphthalic acid, the developed formulacf which is as follows:

-' coon IC/ o-1 tooH itis prepared as follows:

v 10 g. 0! paraphthalic acid are dissolved, .on'

the oil-bath atabout C. in 80 taining 60% of sulphuric anhydride.

This temperature is maintained for 1 hour, after which 40 g. of powdered iodine are added by fractions. v

The temperature is raised to about C. and is maintained for about 5 hours;

At the end of this time; the product of the reaction, which takes place accordingwto the above-mentioned Formula 2, is poured into an excess of cold water. r

The crude tetraiodoparaphthalic acid precipitates.

It is treated with an alkaline solution of potash or soda which dissolves the greater part,

leaving as insoluble a small quantity of hexa-iodo benzene.-

' The solution of potassium or sodium tetraiodeparaphthalate thus obtained, when concentrated by evaporation, will deposit crystals on cooling,

which are purified by fractional crystallization.

The resulting tetraiodo-aoids may be converted into salts of alkali metals, alkali-earth metals. such as sodium or calcium, or of organic bases g. oleum consuch as amines, for instance diethylamine, mono, di or tri ethanolamine or ethylenediamine, thus yielding the following salts, which possess a considerable solubility in water:

B=(CON8)fl Sodium tetraiodometeor parephthaiatc Calcium tetraiodometeor paraphthalate R: ooo-N-omon Monocthanolsmine tetraiodometaor psraphthaiate GHQOHX Dietbanolamine tetraiodometaor paraphthalate s Call a Dicthylamine tetraiodometeor paraphthalate h s 0 o o-ri-o Hi C O O-N- Hi Ht Ethylenediamino tetraiodometeor perephthalete in which R corresponds to the radical Tetraiodometa Tetraiodopara the biliary vesicle and the hepatic canals, the

lymphatic vessels, the space below the arachnoid, fistulas, etc. Further, in the case of the urinary system, they may be administered by intravenous injections, and may be secreted by the reins with the urine, which they render opaque to the X-rays.

A few examples of the use of these products as X-ray contrast agents are given below."

Example 1 6 g. of sodium tetraiodometaphthalate dissolved in 12 c. c. of distilled water, were injected into the marginal vein of the ear of a rabbit weighing 1.96 kg's.

A radiograph taken 15 minutes after, showed the image of the urinary system.

The animal survived, in spite of the injection of a dose of 3.06 g. per kg.

Example 2 A solution of 6 g. of sodium tetraiodometaphthalate in. 100. c. oi. solution injected into human beings by the intravenous method, aifords a radiograph of the urinary system after 5 or 10 minutes.

Example 3" 5.7 g. of sodium tetraiodoparaphthalate dissolved in 19 c. c. of distilled water, were injected into the marginal vein ofthe. ear of a rabbit,

weighing 1.4? kgs.

A radiograph taken 15 minutes after, showed the image of the urinary system.

The animal survived quite well, in spite of the injection oi a dose of substance corresponding to 3.85 g. per kg.

Example 4 A 15% solution of sodium tetraiodoparaphthalate in distilled water, injected by catheterization into the ureters or the renal pelvis. permits of obtaining a pyelograph in the usual m anner.

Example 5 20 c. c. or a solution of 6 g. of sodium tetraiodoparaphthal-ate in distilled watcninjected by the intravenous method. permit of obtaining a radiograph of the urinary system, after 5 to 10 minutes.

Example 6 A solution of 10 g. of triethanolaminetetraiodophthalate, in intravenous injection, permits of obtaining for human beings, a radiograph of the urinary system, after 5 to 10 minutes.

Obviously, the invention is not limited to the specific compounds and the methods of use above mentioned, which are given solely by way of example.

Having now described my invention what I claim as new and desire to secure by Letters Patent is:

1. An X-ray contrast composition containing a water soluble and non-toidc salt of an acid from the group consisting of tetraiodometaphthalic and tetraiodoparaphthalic acids.

2. An X-ray contrast composition containing a water soluble and non-toxic substance of the formula coon in which It represents a basic radical of the group consisting of alkali metals, alkaline earth metals and amines, one of the symbols X, Y representing iodine and the other a second 0003 group. i

3. An X-ray contrast composition containing 4. An X-ray contrast composition containing a water soluble and non-toxic salt formed 01. an a sodium salt of an acid from the group conacld radical from the group consisting of tetrasisting of tetraiodometaphthalic acid and tetraiodometaphthalic and tetraiodoparaphthalic aciii iodoparaphthalic acid. and of abasic radical of the group consisting of 6 alkali metals. alkaline earth metals and amines. ANDRE GASTON JULES GUERBE'I', 

